Gonadotropin releasing hormone (GnRH) is a peptide hormone synthesized in the hypothalamus and it plays an important role in regulating sex-hormones produced by the pituitary gland. Structurally, GnRH is a decapeptide with the amino acid sequence Pyro-Glu1-His2-Trp3-Ser4-Tyr5-Gly6-Leu7-Arg8-Pro9-Gly10-NH2. It is also known in the art as luteinizing hormone releasing hormone (LHRH).
Once GnRH is released from the hypothalamus, it interacts with the surface receptors of pituitary gonadotropes. Once the surface receptors are stimulated, the gonadotropes synthesize and release the so called gonadotropins, luteinizing hormone (LH) and follicle-stimulating hormone (FSH). The significance of these hormones in human reproduction is known. For example, FSH regulates spermatogenesis in males and follicle development in females, and LH regulates gonadal steroid production such as testosterone. Thus, hormone release by the pituitary gland is believed to require prior release of the GnRH decapeptide by the hypothalamus. Since these findings, GnRH analogs that are antagonistic to the normal function of GnRH decapeptide, also known as GnRH antagonists, have been used to suppress secretion of gonadotropins in mammals including humans. Essentially, GnRH antagonists act to lower the circulating levels of FSH and LH.
Of late, a number of GnRH antagonists have been developed for clinical use as agents for controlling testosterone secretion or ovulatory activity and for treating a variety of other hormone-sensitive human conditions such as prostate cancer and endometriosis. The antagonists are also being used for other gynecological purposes particularly to suppress the LH-surge in assisted conception. In terms of action, the GnRH antagonists have been reported to block the access of native GnRH peptides to GnRH receptors and thus suppress gonadotropin production.
In the search for improved GnRH antagonists, the focus has been on reducing the potential for histamine release, maintaining or increasing gonadotropin suppressive potency and increasing water solubility. For example, U.S. Pat. Nos. 5,656,727, 5,516,887, 5,506,207, 5,480,969 and 5,296,468 disclose the design and synthesis of a number of GnRH antagonists. Despite the attractive properties of a number of GnRH antagonists described in the above patents, the search for further improved GnRH antagonists continues. Orntide (DNal1, DpCIPhe2, D3Pal3 Ser4, PicLys5, D(6ANic)Orn6, Leu7, IprLys8, Pro9, DAla10-NH2 (U.S. Pat. Nos. 5,480,969 and 5,656,727; Janecka, et. al., J. Med. Chem., 1994, 37: 2238-2241), an antagonist of GnRH, reportedly is one of the most effective GnRH antagonists developed to date (Jiang et al., Intl. J. Pharmaceutics, 2002, 233: 19-27). It has been reported to have high antigonadotropic potency and low histamine release and relatively favorable water solubility. Still further improved GnRH antagonists, particularly those which exhibit higher water solubility than orntide in a formulation having a pH ranging from about 5 to about 7, more preferably at pH 7.4, and have favorable biological effectiveness would be desirable.